AbstractOverall The Alcohol Research Center of The Scripps Research Institute (TSRI-ARC) proposes to continue its interdisciplinary program focused on the theme of the central nervous system effects of alcohol. For this renewal application, the TSRI-ARC (P60) will consist of 9 components, including 3 Cores (Administrative, Animal Models and Information Dissemination) and 5 Research Projects (Molecular, Neurophysiology, Neurocircuitry,Neurochemistry,andClinical).TheoverallhypothesisoftheTSRI-ARCasanintegratedwhole isthatthecentralstresssystemsbecomeactivatedduringthewithdrawal/negativeaffectstageandpersistinto protracted abstinence (in the preoccupation/anticipation stage), and such neuroadaptive changes associated with chronic drinking also produce an evolving set of neurobehavioral symptoms that include hypohedonia, anxiety,irritability,negativeaffect,hyperarousal,andsleepdisturbances,allofwhichcontributetorelapseand impede recovery. The specific subhypotheses are: 1) The transition from acute withdrawal to protracted abstinence includes compulsive-like responding for ethanol and negative emotional behavior that involves changesininterconnectedbrainareas:theextendedamygdala,themedialprefrontalcortex,andtheanterior insula. 2) The altered activity in these circuits reflects actions of stress-related system including glucocorticoids, serotonin, hypocretin, and corticotropin-releasing factor. 3) Cellular neuroadaptations are associated with altered dynamics of the microtubule cytoskeleton, which may in turn mediate the structural remodelingofneuronaldendrites.4)NovelneurobiologicaltargetsidentifiedbytheTSRI-ARCwillsignificantly attenuate the reinstatement of compulsive-like alcohol seeking, excessive drinking, and anxiety-like behavior;? and5)drugcandidatesforthesetargetswillbeactiveinahumanlabmodelofprotractedabstinencewhere they will reduce drinking, craving, negative affect, and executive function deficits. We believe the proposed innovative approaches for testing these hypotheses will provide valuable insight into novel approaches for treatingalcoholismandrelapseinthehumans. TheTSRI-ARCalsosupportstheCenteratLarge,whichincludes:31R01s,10R21s,3U01s,1U24,2R37s, 2 R13s, and one T32 NIAAA training grant associated with this grant. Members of the Center at Large have access to the Cores of the TSRI-ARC, the NIAAA Integrative Neuroscience Initiative on Alcoholism (INIA) Consortia.TrainingandinformationdisseminationtotheSanDiegocommunitywillbeeffectedbythetraining opportunitiesoftheCenterincludingaT32NIAAAtraininggrantandtheInformationDisseminationCore.